Atherosclerosis, the most common form of vascular disease, is the disorder of large arteries that underlies most coronary artery disease, aortic aneurysm, and arterial disease of lower extremities, and is believed to play a major role in cerebrovascular disease (Libby, in “The Principles of Internal Medicine”, 15th ed., Braunward et al. (editors), Saunders, Philadelphia, Pa., 2001, pp. 1377-1382.). One theory for pathogenesis of atherosclerosis that is consistent with a variety of experimental evidence is the “reaction to injury” hypothesis (Libby, in “The Principles of Internal Medicine”, 15th ed., Braunward et al. (editors), Saunders, Philadelphia, Pa., 2001, pp. 1377-1382.). The injury to the endothelium may be subtle, resulting in a loss of the ability of the cells to function normally. Examples of types of injury to the endothelium include hypercholesterolemia and mechanical stress (Ross, 1999, N. Engl. J. Med., 340: 115). Dysfunction of endothelial cells is believed to trigger a sequence of events including monocyte and platelet adherence, migration of monocytes into intima where they become macrophages, and release of macrophage secretory products, including growth factors and cytokines, which, in conjunction with plasma constituents such as lipoproteins, form foam cells in the vascular wall (Ross, 1999, N. Engl. J. Med., 340: 115). This is believed to stimulate the proliferation of intimal smooth muscle cells at these sites of injury, where these proliferating smooth muscle cells deposit extracellular connective tissue matrix and accumulate lipid, forming an atherosclerotic plaque (Ross, 1999, N. Engl. J. Med., 340: 115).
Percutaneous transluminal coronary balloon angioplasty is a widely used technique for recanalizing arteries that are occluded by atherosclerotic plaque, but its usefulness is limited by the occurrence of restenosis in high proportion of patients (Serruys et al., 1988, Circulation, 77:361). Intracoronary stents have been shown to reduce the incidence of restenosis compared with balloon angioplasty in randomized trials of specific patient groups (Serruys et al., 1994, N. Engl. J. Med., 331:489). The reduction in restenosis achieved with these devices results from greater initial lumen gain, prevention of elastic recoil, and attenuation of the arterial remodeling process (Post et al., 1994, Circulation, 89:2816; Painter et al., 1995, Am. J. Cardiol., 75:398). However, the long-term clinical efficacy of intracoronary stenting is also limited by restenosis, which occurs in 15% to 30% of patients (Serruys et al., 1994, N. Engl. J. Med., 331:489).
In-stent restenosis is believed to be due to neointimal hyperplasia (Serruys et al., 1994, N. Engl. J. Med., 331:489). Stent-induced mechanical arterial injury and a foreign-body response to the prosthesis are believed to result in acute and chronic inflammation in the vessel wall, leading to production of cytokines and growth factors (Serruys et al., 1994, N. Engl. J. Med., 331:489). These are believed to activate multiple signaling pathways, inducing vascular smooth muscle cell (VSMC) proliferation, which is believed to result in neointimal hyperplasia (Serruys et al., 1994, N. Engl. J. Med., 331:489). In addition to VSMC proliferation, VSMC migration and phenotypic differentiation, as well as extracellular matrix formation and degradation are believed to determine the extent of neointimal formation (Newby and George, 1996, Curr. Opin. Cardiol., 11:547). The predominant feature of late restenosis lesions is a large amount of extracellular matrix with a reduced number of smooth muscle cells, whereas in the early stages of intimal thickening formation the number of smooth muscle cells is increased (Pauletto et al., 1994, Clin. Sci., 87:467). To successfully prevent neointimal formation and restenosis, compounds that exert multifactorial effects on cellular activation and extracellular matrix constituents are likely to be necessary, and restenosis prevention using an approach that targets only one causative factor is believed to lack promise (Rosanio et al., 1999, Thromb. Haemost., 82(S1):164).
Drug-eluting or drug-coated stents are a more recent approach to preventing restenosis. Two anti-cancer drugs, sirolimus and paclitaxel, have been used to coat stents, which elute these hyperplasia-inhibiting drugs following implantation (Sousa et al., American Heart Association Scientific Sessions, Nov. 11-14, 2001, Anaheim, Calif., Abstract 115154; Grube et al., American Heart Association Scientific Sessions, Nov. 11-14, 2001, Anaheim, Calif., Abstract 110945). The first human clinical trial with sirolimus-coated stents (the RAVEL trial) followed patients for more than 6 months, with 0 out of 188 patients showing restenosis, and 0 out of 188 patients exhibiting early or late stent thrombosis (Sousa et al., American Heart Association Scientific Sessions, Nov. 11-14, 2001, Anaheim, Calif., Abstract 115154). The efficacy of the paclitaxel-coated stent also appears promising (Honda et al., 2001, Circulation, 104:380). Based on these early results, drug-eluting stents are believed to promise major impact on the treatment of coronary artery disease in the near future.
Both sirolimus and paclitaxel were initially developed as anticancer agents because of their cytostatic ability to inhibit cellular proliferation and migration (Poon et al., 1996, J. Clin. Invest., 98:2277; Rowinsky and Donehower, 1995, N. Engl. J. Med., 332:1004). However, these cytostatic effects are not specific for vascular smooth muscle cells. They were also found to inhibit the proliferation of vascular endothelial cells (Verin at al, 2001, Am. J. Physiol., 281:L565), which may delay endothelialization after stenting resulting in late thrombosis in clinical usage (Liistro and Colombo, 2001, Heart, 86:262).